The goal of this study is to understand molecular basis for genetic and clinical heterogeneity of TDP-43 proteinopathy and to identify genes interacting with TDP-43 that may modify clinical outcomes of TDP-43 proteinopathy. TDP-43 positive neuropathology has been found in a wide range of diseases, including frontotemporal lobar degeneration (FTLD), Alzheimer[unreadable]s disease and amyotrophic lateral sclerosis (ALS) among others. Recent studies have revealed genetic mutations in RNA-binding protein TDP-43 in patients with ALS, although the majority of patients with TDP-43 proteinopathy do not have detectable TDP-43 mutations. These findings highlight the complexity and heterogeneity of TDP-43 proteinopathy. To study biological function and pathological roles of TDP-43, we have established a range of in vitro biochemical, molecular and cell biological assays to examine the wild type TDP-43 function and effects of ALS-associated TDP-43 mutations. Using transgenic flies expressing human TDP-43, we have established a Drosophila model that recapitulates a number of neuropathological and clinical features of TDP-43 proteinopathy. We have begun to use a combined approach to identify factors interacting with TDP-43 and begun to construct signaling pathways/networks that TDP-43 is involved in. We propose to systematically search for genes interacting with TDP-43 and to identify genetic modifiers of TDP-43 proteinopathy using our transgenic fly model. Our work will not only help elucidate pathogenic mechanisms underlying this disease but also suggest future therapeutic targets specific to TDP-43-dependent signaling pathways.